Project Summary The MYC oncogene is overexpressed in some of the most aggressive and difficult to treat human cancers, including receptor triple-negative breast cancers (TNBCs), as well as high-grade lymphomas and aggressive subtypes of liver cancers. MYC overexpression induces a highly malignant state by driving proliferation and altering various metabolic programs within tumor cells. We recently discovered that MYC-driven transgenic models of breast cancer have reprogramed cellular metabolism that favor fatty acid oxidation (FAO) as an energy source. This finding was also observed in MYC-high TNBCs and has recently been confirmed by an independent research group. Targeting FAO in human cell lines, MYC-driven transgenic animal models and patient-derived xenograft (PDX) models of breast cancer results in diminished tumor growth and increased cell death. What remains unknown is what are the molecular mechanisms through which MYC reprograms tumor metabolism to favor FAO. Furthermore, we seek to understand why MYC-high tumors are dependent on the FAO pathway for their growth and survival. Finally, we seek to improve upon current therapies for TNBCs by performing advance preclinical studies in PDX models to determine if blocking FAO alone or in combination with other metabolic pathways in vivo will provide improved therapeutic response. Our studies will improve our understanding of how MYC reprograms metabolism in vivo and will lead to novel therapeutics for difficult to treat MYC overexpressing cancers.